HIV ONCOLOGY HANDBOOK. Antiretroviral Interactions with Chemotherapy Regimens. Alison Wong, B.pharm., M.Sc. Alice Tseng, Pharm.D.

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1 2014 HIV ONCOLOGY HANDBOOK Antiretroviral Interactions with Chemotherapy Regimens Alison Wong, B.pharm., M.Sc. Chronic Viral Illness Service McGill University Health Centre Montreal, QC Alice Tseng, Pharm.D., FCSHP, AAHIVP Immunodeficiency Clinic Toronto General Hospital Toronto, ON

2 2014 HIV ONCOLOGY HANDBOOK Antiretroviral Interactions with Chemotherapy Regimens Alison Wong, B.pharm., M.Sc. Chronic Viral Illness Service McGill University Health Centre Montreal, QC Alice Tseng, Pharm.D., FCSHP, AAHIVP Immunodeficiency Clinic Toronto General Hospital Toronto, ON Copyright 2014, A. Wong & A. Tseng. All rights reserved. All material in this handbook is copyrighted by the author and may be reprinted only with written permission of the author. Requests to reprint or reproduce material may be sent by fax or to Alice Tseng, Pharm.D., Immunodeficiency Clinic, Toronto General Hospital, , Additional information and updates may be found at:

3 TABLE OF CONTENTS ACKNOWLEDGEMENTS i INTRODUCTION ii PRINCIPLES OF HIV THERAPY ANTIRETROVIRAL INTERACTIONS WITH CHEMOTHERAPY REGIMENS: Aggressive histology non-hodgkin s lymphoma [NHL]: CHOP CNS LYMPHOMA CODOX-M...13 CVP DA-EPOCH Hyper CVAD IVAC Hodgkin s Lymphoma: ABVD BEACOPP/escalated BEACOPP Relapsed Hodgkin s or aggressive histology NHL (salvage chemotherapy regimens): DHAP ESHAP GDP ICE MINIBEAM ANTIRETROVIRAL INTERACTIONS WITH SUPPORTIVE THERAPY Summary of interactions 65 Interactions with Anti-Emetics Aprepitant (Emend ) Selective 5-HT 3 Receptor antagonists...67 Dimenhydrinate/diphenhydramine Steroids Dexamethasone Methylprednisolone Prednisone...69 Acid suppressants 70 Miscellaneous Fluconazole Acyclovir Allopurinol...71 References 71 GLOSSARY TABLE OF CONTENTS

4 ACKNOWLEDGEMENTS Contributors We would like to gratefully acknowledge the contributions of the following reviewers from the Princess Margaret Cancer Centre, University Health Network: Pamela Ng, B.Pharm. Jack Seki, B.Pharm., Pharm.D. Vishal Kukreti, MD., FRCPC Sharon Walmsley, MD, FRCPC This work would not have been possible without their support and assistance. Sponsorship The print production of the 2014 HIV Oncology Handbook was made possible through the support of Merck Canada Inc. and ViiV Canada. The opinions expressed in this material are those of the authors and do not necessarily reflect the views of Merck Canada Inc. or ViiV Canada. Distribution The 2014 HIV Oncology Handbook is available in print and e-book versions. The information in this book is also available at: and is updated on a regular basis. Disclaimer The information in this Handbook is intended for use by and with experienced physicians and pharmacists. The information is not intended to replace sound professional judgment in individual situations, and should be used in conjunction with other reliable sources of information. Due to the rapidly changing nature of information about HIV treatment and therapies, users are advised to recheck the information contained herein with the original source before applying it to patient care. Decisions about particular medical treatments should always be made in consultation with a qualified medical practitioner knowledgeable about HIVrelated illness and the treatments in question. Neither McGill University Health Centre, University Health Network, nor the authors and contributors are responsible for deletions or inaccuracies in information or for claims of injury resulting from any such deletions or inaccuracies. Mention of specific drugs, drug doses or drug combinations within this book does not constitute endorsement by the authors, McGill University Health Centre or University Health Network. i ACKNOWLEDGEMENTS

5 INTRODUCTION Clinically significant interactions between chemotherapy regimens and antiretroviral therapy have been reported in the literature. In particular, the use of protease-inhibitor based antiretroviral treatment has been shown to increase the toxicity of several chemotherapy agents, primarily those which are known substrates of the cytochrome P450 system and/or p-glycoprotein. Similar concerns may also apply to antiretroviral regimens containing the pharmacokinetic enhancer, cobicistat as both protease-inhibitor based antiretroviral treatment and cobicistat are considered to be moderate-potent inhibitors of cytochrome P450 enzymes. Conversely, most non-nucleoside reverse transcriptase inhibitors are moderate-potent inducers of cytochrome P450 enzymes, and could potentially reduce exposures of certain chemotherapy agents. However, clinical data on such combinations are much more limited. Since standardized dosing algorithms do not exist for managing such interactions, increased monitoring for efficacy and toxicity is recommended when co-administering any chemotherapy regimen with antiretroviral therapy. Purpose This reference guide is intended to serve as a practical summary of available literature regarding interactions between antiretroviral agents and chemotherapy regimens and supportive therapy for lymphoma management. Due to the scarcity of available literature and the variability of the quality of evidence, clinical management should be assessed individually for each patient. It is hoped that this information will increase the awareness of possible interactions between antiretrovirals and chemotherapy agents and promote communication between pharmacists and physicians of both specialized sectors. Interdisciplinary collaboration would allow clinicians to more effectively manage the interactions according to each situation, with the potential benefits of optimally treating both the oncology diagnoses and HIV infection while minimizing the risk of toxicity and adverse outcomes for the patient. Future studies are essential to further evaluate the impact of these interactions. Data An exhaustive review of currently published literature was conducted through Ovid Medline 1948 November 2013 using MeSH terms for individual chemotherapy agents, keywords for chemotherapy regimens, and the following MeSH terms for HIV (HIV, Anti-HIV agents). Identification of pertinent references in the gray literature was done through the International AIDS Society USA abstract search engine. Quality of evidence was evaluated according to an adapted GRADE system. Summary Potential pharmacokinetic and pharmacodynamic interactions may occur between chemotherapy agents and antiretrovirals. Pharmacokinetic interactions may affect concentrations of one or both drugs, possibly leading to increased toxicity and/or decreased efficacy. Pharmacodynamic interactions may occur when agents with similar side effect profiles are co-administered, and may lead to increased toxicity. The following table summarizes the most commonly encountered types of interactions between antineoplastics and antiretrovirals. This table is not all-inclusive; readers are urged to consult the specific chemotherapy regimen summaries in this guide for more specific information. INTRODUCTION ii

6 administered, and may lead to increased toxicity. The following table summarizes the most commonly encountered types of interactions between antineoplastics and antiretrovirals. This table is not all-inclusive; readers are urged to consult the specific chemotherapy regimen summaries in this guide for more specific information. iii Antiretrovirals Involved (examples) Pharmacokinetic Interactions Inhibition of Protease CYP450 Inhibitors enzymes (including atazanavir, darunavir, lopinavir, ritonavir) cobicistat Induction of Non-nucleoside CYP450 reverse enzymes transcriptase inhibitors (including Antiretrovirals efavirenz, Involved nevirapine, (examples) etravirine, rilpivirine) Pharmacodynamic Interactions Bone marrow Zidovudine suppression Peripheral neuropathy INTRODUCTION Didanosine, stavudine Chemotherapy Agents (examples) CYP3A4 substrates: dexamethasone, etoposide, vincristine, vinblastine, others As above. Chemotherapy Agents (examples) Vinca alkaloids Renal toxicity Tenofovir Cisplatin Cytarabine Methotrexate Increase in serum creatinine Cobicistat, dolutegravir, rilpivirine This effect does not target any specific chemotherapy agent. These agents however may cause an asymptomatic increase in secrum creatinine due to inhibition of tubular creatinine secretion. Management Monitor for increased chemotherapy toxicity. Adjust dose or consider replacing antiretrovirals with alternate agents.* Monitor for response to chemotherapy. Adjust dose or consider Management replacing antiretrovirals with alternate agents.* Potential for overlapping toxicity. Adjust dose or consider replacing antiretrovirals with alternate agents.* Potential for overlapping toxicity. Adjust dose or consider replacing antiretrovirals with alternate agents.* Increase in serum creatinine appears within first few weeks of treatment and then remains stable; actual GFR is not affected. If further changes in serum creatinine are observed, consider other causes. *modifications to antiretroviral treatment should be done in consultation *modifications to antiretroviral treatment should be done in consultation with a physician and/or pharmacist experienced with a physician in HIV care. and/or pharmacist experienced in HIV care. Disclaimer: Considering the rapidly evolving literature in the HIV domain, clinicians are invited to consult the primary literature for the most accurate information. Disclaimer: Considering the rapidly evolving literature in the HIV domain, clinicians are invited to consult the primary literature for the most accurate information.

7 PRINCIPLES OF HIV THERAPY The intent of this section is to summarize the principles of HIV treatment in the context of treating a concomitant cancer diagnosis. Summary All patients receiving chemotherapy should receive concomitant antiretroviral therapy (cart) cart consists of three or more active antiretroviral agents Individual agents should not be stopped Changes in antiretroviral therapy should be done in consultation with an HIV specialist, as knowledge of the patient s complete treatment history including resistance data is essential when devising alternate antiretroviral treatment options Primary prophylaxis of opportunistic infection may be required depending on the CD4 count Should patients be on antiretroviral therapy? Patients not previously on antiretroviral treatment For patients not previously treated with antiretrovirals, two scenarios are possible. The patient could either be newly diagnosed with HIV at the time of diagnosis of the malignancy or the patient was previously known HIV but was not receiving antiretroviral treatment. In both situations, the patient should be started on antiretroviral treatment and should be maintained on antiretroviral therapy throughout chemotherapy. Concomitant administration of both antiretroviral therapy and chemotherapy has been shown to increase survival rates (1-5). Patients previously on antiretroviral treatment These patients should continue antiretroviral treatment during chemotherapy as interruption of treatment has been shown to increase mortality (6). In addition, HIV-HBV co-infected patients may be on antiretroviral therapy that treats both viruses. If HBV therapy is stopped, this could result in a hepatic flare possibly resulting in fulminant hepatitis (7). Antiretroviral therapy should not be changed without consulting the patient s HIV physician as full treatment history of the patient and resistance data of the virus must be taken into consideration to maintain an effective treatment. Risk of interactions between antiretroviral therapy and chemotherapy Antiretroviral agents have a high risk of interaction with numerous drugs due to their effect on the metabolism. Interactions between antiretroviral and chemotherapy agents are not well documented and no clear recommendations on the management of these interactions have been proposed. Nevertheless, interruption of therapy is not recommended as this has been associated with an increase in mortality (6). Cessation of an individual antiretroviral thought to interact with the chemotherapy is contra-indicated as this will decrease the efficacy of the antiretroviral regimen and promote the development of resistance to the agents that will be continued. However, in many instances, one or more components of a patient s antiretroviral regimen may be substituted in order to avoid risk of drug interaction or additive toxicity. For instance, certain nucleoside analogues are associated with side effects that may overlap with anticipated toxicities of chemotherapy, e.g: Zidovudine(Retrovir, Combivir, Trizivir ): risk of additive hematologic toxicity (8) Stavudine (Zerit ): risk of additive peripheral neuropathy (9) Didanosine (Videx EC ): risk of additive peripheral neuropathy (10) PRINCIPLES OF HIV TREATMENT 1

8 Stavudine (Zerit ): risk of additive peripheral neuropathy (9) Didanosine (Videx EC ): risk of additive peripheral neuropathy (10) It is important to contact the patient s HIV physician in order to discuss a change in therapy. It is important not to stop this agent alone or to empirically substitute this It is agent important with to another contact as the a patient s change HIV in antiretroviral physician in order therapy to discuss should a only change be in done therapy. with It is important the patient s not to stop complete this agent antiretroviral alone or to empirically history and substitute resistance this data. agent with another as a change in antiretroviral therapy should only be done with the patient s complete antiretroviral history and Principles of treatment resistance data. Standard HIV treatment generally consists of a combination of three or more active Principles drugs, two of nucleos(t)ide treatmentreverse transcriptase inhibitors (NRTIs) and a third agent from one of the other classes. However, some patients may present with atypical Standard HIV treatment generally consists of a combination of three or more active drugs, two nucleos(t) regimens. Please refer to the most current HIV treatment guidelines at: ide reverse transcriptase inhibitors (NRTIs) and a third agent from one of the other classes. However, some at: patients may present with atypical regimens. Please refer to the most current HIV treatment guidelines It is important to note that Norvir (ritonavir) and Tybost (cobicistat) are generally given to increase It is important to note that Norvir (ritonavir) and Tybost (cobicistat) are the generally plasma concentrations given to increase of other the antiretroviral plasma concentrations agents. Norvir of other (ritonavir) antiretroviral and Tybost agents. (cobicistat) should Norvir therefore (ritonavir) not be considered and Tybost as an (cobicistat) active drug. should therefore not be considered as an active drug. Single Tablet Regimens Ingredients Atripla Complera Stribild Efavirenz, tenofovir, emtricitabine Rilpivirine, tenofovir, emtricitabine Elvitegravir, cobicistat, tenofovir, emtricitabine N(t)RTI PI NNRTI 3TC (lamivudine) Aptivus (tipranavir) Edurant (rilpivirine) Retrovir (zidovudine) Crixivan (indinavir) Intelence (etravirine) Videx EC (didanosine) Invirase (saquinavir) Sustiva (efavirenz) Viread (tenofovir) Kaletra (lopinavir/ritonavir) Viramune (nevirapine) Ziagen (abacavir) Prezista (darunavir) Zerit (stavudine) Reyataz (atazanavir) CCR5 antagonist Combinations Telzir (fosamprenavir) Celsentri (maraviroc) Combivir (zidovudine, lamivudine) Kivexa (abacavir, lamivudine) Trizivir (abacavir,zidovudine, lamivudine) Truvada (tenofovir, emtricitabine) Viracept (nelfinavir) Pharmacokinetic enhancers Integrase inhibitors (booster) Norvir (ritonavir)* Tybost (cobicistat) Isentress (raltegravir) Tivicay (dolutegravir) Vitekta (elvitegravir) *Ritonavir belongs to the protease inhibitor class, but it is generally used at low doses to act *Ritonavir belongs to the protease inhibitor class, but it is generally used at low doses to act as a as a pharmacokinetic enhancer, and is not considered an active antiretroviral drug. pharmacokinetic enhancer, and is not considered an active antiretroviral drug. N(t)RTI: nucleos(t)ide reverse reverse transcriptase transcriptase inhibitor; inhibitor; PI: protease PI: inhibitor; protease NNRTI: inhibitor; non-nucleoside NNRTI: nonnucleoside transcriptase reverse inhibitor; transcriptase CCR5: inhibitor; C-C chemokine CCR5: receptor C-C chemokine 5 receptor reverse PRINCIPLES OF HIV TREATMENT

9 Risk of opportunistic infections Risk of opportunistic infections HIV-infected patients may have an increased risk of infection in comparison to the general population depending HIV-infected on their patients CD4 count. may Thresholds have an for increased initiating risk primary of infection prophylaxis in of comparison opportunistic to infections the are general as follows population (11): depending on their CD4 count. Thresholds for initiating primary prophylaxis of opportunistic infections are as follows (11): CD4 (cells/mm 3 ) 0 50 Pneumocystis jirovecii pneumonia TMP-SMX DS 1 tab Qday Toxoplasmosis gondiiencephalitis (if Azithromycin 1200 mg IgG +) Qweek Mycobacterium aviumcomplex * Note: alternative dosing regimens are possible Note: alternative dosing regimens are possible Comment on Rituximab count Opportunistic infections 200 None None Primary prophylaxis Pneumocystis jirovecii pneumonia TMP-SMX DS 1 tab Qday* Pneumocystis jirovecii pneumonia TMP-SMX DS 1 tab Qday Toxoplasmosis gondiiencephalitis (if IgG +) References 1. Diamond C, Taylor TH, Im T, Anton-Culver H. Presentation and outcomes of Rituximab, systemic a monoclonal non-hodgkin's antibody directed lymphoma: against a CD20, comparison often between used for patients treatment with of non- Hodgkin s acquired lymphoma immunodeficiency in immunocompetent syndrome patients. Though (AIDS) no treated pharmacokinetic with highly interactions active with antiretroviral therapy and patients without AIDS. Leuk Lymphoma. antiretroviral 2006;47(9): agents are expected, its use in the HIV population is less well defined considering the potential 2. increased Navarro JT, risk Ribera of mortality JM, due Oriol to A, infectious Romeu causes. J, Sirera G, Mate JL, et al. Favorable impact of virological response to highly active antiretroviral therapy on A recent pooled survival analysis in patients of 1546 patients with completed AIDS-related by Barta lymphoma. SK et al evaluated Leuk treatment Lymphoma. factors affecting outcomes 2002;43(9): in HIV-associated non-hodgkin s lymphoma. The authors showed that the use of 3. Mounier N, Spina M, Gabarre J, Raphael M, Rizzardini G, Golfier JB, et al. rituximab in patients with CD4 counts 50 cells/µl increased the odds of complete response by 2.84 AIDS-related non-hodgkin lymphoma: final analysis of 485 patients treated times (p < with 0.001). risk-adapted This improvement intensive was chemotherapy. not observed in patients Blood. with 2006;107(10): a CD4 count < 50 cells/µl and may 4. be due Weiss to an R, increased Mitrou risk P, Arasteh of infectious K, Schuermann deaths due to D, use Hentrich of rituximab. M, Duehrsen (12) U, et al. Acquired immunodeficiency syndrome-related lymphoma: simultaneous Of note, use treatment of rituximab with may combined be restricted cyclophosphamide, in certain provinces doxorubicin, in Canada. Verification vincristine, of medication and coverage by prednisone patient s insurance chemotherapy is essential and prior highly to active prescribing antiretroviral this agent. therapy is safe and improves survival--results of the German Multicenter Trial. Cancer. 2006;106(7): References 5. Navarro JT, Ribera JM, Oriol A, Vaquero M, Romeu J, Batlle M, et al. Influence 1. Diamond of highly C, Taylor active TH, Im anti-retroviral T, Anton-Culver therapy H. Presentation response and outcomes to treatment of systemic and survival non- Hodgkin s patients lymphoma: with a comparison acquired immunodeficiency between patients with syndrome-related acquired immunodeficiency non-hodgkin's lymphoma treated with cyclophosphamide, hydroxydoxorubicin, vincristine syndrome (AIDS) treated with highly active antiretroviral therapy and patients without AIDS. and prednisone. Br J Haematol. 2001;112(4): Leuk Lymphoma. 2006;47(9): Navarro JT, Ribera JM, Oriol A, Romeu J, Sirera G, Mate JL, et al. Favorable impact of virological response to highly active antiretroviral therapy on survival in patients with AIDSrelated lymphoma. Leuk Lymphoma. 2002;43(9): Mounier N, Spina M, Gabarre J, Raphael M, Rizzardini G, Golfier JB, et al. AIDS-related non- Hodgkin lymphoma: final analysis of 485 patients treated with risk-adapted intensive chemotherapy. Blood. 2006;107(10): PRINCIPLES OF HIV TREATMENT 3

10 4. Weiss R, Mitrou P, Arasteh K, Schuermann D, Hentrich M, Duehrsen U, et al. Acquired immunodeficiency syndrome-related lymphoma: simultaneous treatment with combined cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy and highly active antiretroviral therapy is safe and improves survival--results of the German Multicenter Trial. Cancer. 2006;106(7): Navarro JT, Ribera JM, Oriol A, Vaquero M, Romeu J, Batlle M, et al. Influence of highly active anti-retroviral therapy on response to treatment and survival in patients with acquired immunodeficiency syndrome-related non-hodgkin s lymphoma treated with cyclophosphamide, hydroxydoxorubicin, vincristine and prednisone. Br J Haematol. 2001;112(4): El-Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D, Arduino RC, et al. CD4+ countguided interruption of antiretroviral treatment. The New England journal of medicine. 2006;355(22): Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at 8. Retrovir. Product monograph. GlaxoSmithKline; Zerit. Product monograph. Bristol-Myers Squibb Canada; Videx Ec. Product monograph. Bristol-Myers Squibb Canada; Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Updated July 8, Available at: Barta SK, Xue X, Wang D, Tamari R, Lee JY, Mounier N, et al. Treatment factors affecting outcomes in HIV-associated non-hodgkin lymphomas : a pooled analysis of 1546 patients. Blood 2013; 122(19): PRINCIPLES OF HIV TREATMENT

11 ANTIRETROVIRAL INTERACTIONS WITH CHEMOTHERAPY REGIMENS Aggressive histology non-hodgkin s lymphoma [NHL]: CHOP 5 CNS LYMPHOMA 9 CODOX-M 13 CVP 17 DA-EPOCH 21 Hyper CVAD 25 IVAC 31 ANTIRETROVIRAL INTERACTIONS WITH CHEMOTHERAPY REGIMENS

12 Antiretroviral-Chemotherapy Interactions: CHOP Regimen Chemotherapy regimen: CHOP Agents involved Doxorubicin 50 mg/m 2 IV Day 1 Vincristine 1.4 mg/m 2 IV Day 1 Cyclophosphamide 750 mg/m 2 IV in 250 ml of NS Day 1 Prednisone 100 mg po daily Day 1 5 Summary of possible interactions with antiretroviral agents Antiretroviral agents to avoid Avoid zidovudine-containing regimens (Retrovir, Combivir, Trizivir ) as additive hematologic toxicity is possible (1-3). (Quality of Evidence: very low) Avoid stavudine (Zerit ), didanosine (Videx EC ) due to possible additive peripheral neuropathy (4, 5). (Quality of Evidence: very low) If the patient is on one of the antiretroviral agents mentioned above, contact the HIV physician to request a change/substitution of antiretroviral agents. Enzyme inhibition interactions 1 Possible increased vincristine toxicity (autonomic neurotoxicity) (6, 7) (Quality of Evidence: moderate) Possible increased cyclophosphamide toxicity due to decreased clearance (Quality of Evidence: very low; pharmacokinetic study of unknown clinical significance) (8) Enzyme induction interactions 2 (Quality of Evidence: very low; theoretical, unknown clinical significance) Possible decreased efficacy of doxorubicin and vincristine (9, 10) Possible decreased efficacy and increase in cyclophosphamide toxicity due to increased inactivation to toxic metabolites (9, 10) Enzyme neutral agents 3 : unlikely to interact (Quality of Evidence: very low; theoretical) According to the metabolic profile of the individual agents, pharmacokinetic interactions are unlikely to occur. Nonetheless, additive toxicity remains possible with certain agents depending on the safety profile. Laboratory interactions (Quality of Evidence: high; no clinical significance) Cobicistat (Stribild, Tybost ), rilpivirine (Edurant, Complera ) and dolutegravir (Tivicay ) containing regimens will increase serum creatinine by approximately 7-15 µmol/l during the first 4 weeks of treatment initiation due to inhibition of renal creatinine secretion. This does not reflect an actual decrease in renal function, and the effect is quickly reversible upon drug discontinuation. Note: if interruption of any antiretroviral agent is considered necessary, contact the HIV physician to determine appropriate cessation of the antiretroviral therapy (certain antiretroviral regimens require sequential cessation of antiretroviral agents while others require immediate cessation of all antiretroviral agents at once). If treatment for hepatitis B (HBV) co-infection is required, consult the HIV physician, since some antiretroviral agents have activity against both HIV and HBV. AGGRESSIVE HISTOLOGY NON-HODGKIN S LYMPHOMA - CHOP 5

13 Antiretroviral-Chemotherapy Interactions: CHOP Regimen Literature One study evaluated the clinical impact of co-administration of combination antiretroviral therapy (cart) with CHOP in the context of treatment for non-hodgkin s lymphoma. They did not observe any difference in response rates, dose intensity or number of cycles of chemotherapy when CHOP was coadministered with 24 patients on a PI based cart (saquinavir, indinavir or ritonavir) in comparison to the 80 patients on CHOP alone. They did observe, however, an increased risk of grade 3 or 4 anemia and autonomic neurotoxicity. No difference was noted in regards to leucopenia, thrombocytopenia, mucositis or nausea. (6) It is important to note, however, that 58% of patients receiving cart had zidovudine in their regimen, likely explaining the increased risk of anemia. Regarding the impact of CHOP on antiretroviral concentrations, one study also showed that the administration of CHOP and indinavir-based cart resulted in an increase of indinavir AUC in comparison to when indinavir was given without CHOP. No excess of toxicity was observed however (11). In contrast, another study showed a lower indinavir AUC when given with CHOP in comparison to a historical cohort. The decrease in HIV viral load and increase in CD4 count was considered to be similar to HIV patients without malignancies. (8) Pharmacokinetic studies Two studies evaluated the influence of cart on the pharmacokinetics of doxorubicin in the context of CHOP for the treatment of non-hodgkin s lymphoma. One study in 19 patients reported no significant difference in doxorubicin pharmacokinetic parameters when patients used saquinavir, nelfinavir or indinavir in addition to two nucleoside reverse transcriptase inhibitors.(12) Another study in 29 patients showed similar clearance rates of doxorubicin when administered with an indinavir-based cart.(8) The same study evaluated the pharmacokinetics of cyclophosphamide. Co-administration with indinavirbased cart resulted in a decrease of cyclophosphamide clearance from 70 to ml/min/m 2. This however, did not translate into excessive toxicity. (8) No pharmacokinetic studies regarding interactions between antiretrovirals and vincristine, prednisone were identified. Case reports Administration with lopinavir/ritonavir Two cases described good tolerability of dose-adjusted EPOCH (etoposide 200 mg/m 2, vincristine 1.6 mg/m 2, cyclophosphamide 748 mg/m 2, doxorubicin 40 mg/m 2 continuous infusion over 4 days, prednisone 60 mg/m 2 daily for 5 days) when administered with lopinavir/ritonavir for treatment of anaplastic large-cell lymphoma. Vincristine, cyclophosphamide and doxorubicin doses were similar to those used in CHOP. (13) One case report described increased vincristine toxicity in the context of co-administration of CODOX- M (vincristine 4 mg IV, doxorubicin 40 mg/m 2 IV, cyclophosphamide 1600 mg/m 2 IV, cytarabine 140 mg IT, methotrexate 6720 mg/m 2 IV and methotrexate 15 mg IT per cycle) and lopinavir/ritonavir. The patient received one cycle of CODOX-M for treatment of Burkitt s lymphoma while on lopinavir/ritonavir based cart. On Day 12, the patient developed paralytic ileus which lasted for 10 days. Of note, vincristine dose administered was greater than that of CHOP. Two weeks after recovery, IVAC (ifosfamide 7.5 g/m 2 ; etoposide 300 mg/m 2 ; cytarabine 8 g/m 2 ) was administered with no complications. Two months after the first cycle, the patient was given CODOX-M; however, the vincristine component was changed to etoposide. This regimen, which included a similar dose of doxorubicin and a higher dose of cyclophosphamide compared to CHOP, was well tolerated. (7) Administration with raltegravir One case report described good tolerability of CHOP when administered with abacavir, lamivudine and raltegravir, a non-pi, non-nnrti based antiretroviral regimen (14). Another case series of 7 patients also described good CHOP tolerability when administered with tenofovir, emtricitabine and raltegravir (15). 6 AGGRESSIVE HISTOLOGY NON-HODGKIN S LYMPHOMA - CHOP

14 Antiretroviral-Chemotherapy Interactions: CHOP Regimen Metabolism of chemotherapy agents Chemotherapy agent Metabolism(9, 10) Possible interaction(9, 10) Clinical evidence Doxorubicin Aldoketoreductase and NADPH-dependent cytochrome reductase. Resulting aglycone derivatives (inactive metabolites) conjugated to a sulfate or glucuronide metabolite. Enzymes of cytochrome P450 involved in free radical generation in vitro; substrate of PgP which may influence intracellular concentrations; clinical significance unknown. Enzyme inhibitors may decrease reduction to free radicals via inhibition of cytochrome P450 which may decrease both antineoplastic and cytotoxic properties; however, they may also increase intracellular accumulation of doxorubicin via inhibition of PgP, which may enhance cytotoxic effects and/or systemic toxicity. Enzyme inducers may do the opposite. Vincristine CYP 3A4 Possibility of increased levels leading to increased toxicity (peripheral and autonomic neuropathy, myelosuppression) with CYP 3A4 inhibitors. Possibility of decreased levels with 3A4 inducers. Cyclophosphamide Transformation to active metabolite: CYP2B6, 2C19 Transformation to inactive and possibly toxic metabolites: CYP 3A4 Prednisone Converted to active metabolite prednisolone by non-cyp mediated route. Prednisone and prednisolone are also substrates of CYP 450 including CYP 3A4. Ritonavir, nelfinavir, efavirenz and nevirapine may increase the amount of active metabolites formed by induction of CYP 2B6 leading to increased efficacy and toxicity of cyclophosphamide. Inhibition of 3A4 may increase drug availability for hydroxylation route thereby leading to increased efficacy and toxicity of cyclophosphamide. Induction of CYP 3A4 may increase neurotoxicity. Possible increased toxicity with CYP 3A4 inhibitors. Possible decreased efficacy with CYP 3A4 inducers. No change. Doxorubicin pharmacokinetics (context of CHOP) not affected by PI administration.(8, 12) Possible increased risk of autonomic neurotoxicity when administered with a PI based regimen. (6, 7) Good tolerability in 2 cases with lopinavir/ritonavir and DA- EPOCH for treatment of anaplastic large-cell lymphoma.(13) Decreased clearance of cyclophosphamide when administered with PIs. No excess toxicity observed.(8) No evidence of increased toxicity found in the published literature. Please consult for more updated information. AGGRESSIVE HISTOLOGY NON-HODGKIN S LYMPHOMA - CHOP 7

15 Antiretroviral-Chemotherapy Interactions: CHOP Regimen References 1. Retrovir. Product monograph. GlaxoSmithKline; Combivir. Product Monograph. GlaxoSmithKline; Trizivir. Product Monograph. GlaxoSmithKline; Zerit. Product monograph. Bristol-Myers Squibb Canada; Videx Ec. Product monograph. Bristol-Myers Squibb Canada; Vaccher E, Spina M, di Gennaro G, Talamini R, Nasti G, Schioppa O, et al. Concomitant cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy plus highly active antiretroviral therapy in patients with human immunodeficiency virus-related, non-hodgkin lymphoma. Cancer Jan 1;91(1): Leveque D, Santucci R, Pavillet J, Herbrecht R, Bergerat JP. Paralytic ileus possibly associated with interaction between ritonavir/lopinavir and vincristine. Pharm World Sci Dec;31(6): Ratner L, Lee J, Tang S, Redden D, Hamzeh F, Herndier B, et al. Chemotherapy for human immunodeficiency virusassociated non-hodgkin's lymphoma in combination with highly active antiretroviral therapy. J Clin Oncol Apr 15;19(8): Antoniou T, Tseng A. Potential interactions between antineoplastics and antiretrovirals. In: Tseng A, Foisy M, editors. Handbook of HIV drug therapy ed. Toronto2010. p Antoniou T, Tseng AL. Interactions between antiretrovirals and antineoplastic drug therapy. Clin Pharmacokinet. 2005;44(2): Cruciani M, Gatti G, Vaccher E, Di Gennaro G, Cinelli R, Bassetti M, et al. Pharmacokinetic interaction between chemotherapy for non-hodgkin's lymphoma and protease inhibitors in HIV-1-infected patients. J Antimicrob Chemother Apr;55(4): Toffoli G, Corona G, Cattarossi G, Boiocchi M, Di Gennaro G, Tirelli U, et al. Effect of highly active antiretroviral therapy (HAART) on pharmacokinetics and pharmacodynamics of doxorubicin in patients with HIV-associated non-hodgkin's lymphoma. Ann Oncol Dec;15(12): Nagajothi N, Dham SK, Gelfand Y, Sanmugarajah J. Treatment of AIDS-associated anaplastic large-cell lymphoma with dose-adjusted EPOCH chemotherapy. J Natl Med Assoc. [Case Reports] Jul;99(7): Fulco PP, Hynicka L, Rackley D. Raltegravir-based HAART regimen in a patient with large B-cell lymphoma. Ann Pharmacother. Feb;44(2): Marcotte S, Laroche M, Turcotte I, Fortin C, Lessard B, Trottier B, et al. Raltegravir-based-HAART and lymphoma chemotherapy. XVIII International Aids Conference; Vienna, Austria Enzyme inhibitors include protease inhibitors (PIs): Crixivan (indinavir), Invirase (saquinavir), Kaletra (lopinavir/ritonavir), Norvir, Norvir sec (ritonavir), Prezista (darunavir), Reyataz (atazanavir), Telzir (fosamprenavir), Viracept (nelfinavir); and the integrase inhibitor elvitegravir/cobicistat: available as a coformulated product with tenofovir/emtrictabine (Stribild ); pharmacokinetic enhancer cobicistat (Tybost ). 2 Enzyme inducers include non-nucleside reverse transcriptase inhibitors (NNRTIs): Atripla (efavirenz/tenofovir/emtricitabine), Complera (rilpivirine/tenofovir/emtricitabine), Edurant (rilpivirine), Intelence (etravirine), Sustiva (efavirenz), Viramune, Viramune XR (nevirapine) and the protease inhibitor Aptivus (tipranavir) 3 Enzyme neutral agents include nucleoside reverse transcriptase inhibitors (NRTIs) : 3TC (lamivudine), Combivir (lamivudine/zidovudine), Kivexa (abacavir/lamivudine), Retrovir (zidovudine), Trizivir (abacavir/zidovudine/lamivudine), Truvada (tenofovir/emtricitabine), Videx EC (didanosine), Zerit (stavudine); integrase inhibitors Isentress (raltegravir), Tivicay (dolutegravir); entry inhibitors Fuzeon (enfuvirtide), Celsentri (maraviroc) 8 AGGRESSIVE HISTOLOGY NON-HODGKIN S LYMPHOMA - CHOP

16 Antiretroviral-Chemotherapy Interactions: CNS lymphoma regimen Chemotherapy regimen: CNS lymphoma High-dose methotrexate protocol Agents involved Methotrexate 3500 mg/m 2 IV in 500 ml of D5W Day 1 Vincristine 1.4mg/m 2 IV in 50 ml of NS Day 1 (odd cycles) Procarbazine 100 mg/m 2 po qhs Day 1-7 (odd cycles) Summary of possible interactions with antiretroviral agents Antiretroviral agents to avoid Avoid zidovudine-containing regimens (Retrovir, Combivir, Trizivir ) as additive hematologic toxicity is possible (1-3). (Quality of Evidence: very low) Avoid stavudine (Zerit ), didanosine (Videx EC ) due to possible additive peripheral neuropathy (4, 5). (Quality of Evidence: very low) If the patient is on one of the antiretroviral agents mentioned above, contact the HIV physician to request a change/substitution of antiretroviral agents. Enzyme inhibition interactions 1 Possible increased vincristine toxicity (autonomic neurotoxicity) (6, 7) (Quality of Evidence: moderate) Possible increased procarbazine toxicity (8, 9) (Quality of Evidence: very low; theoretical, unknown clinical significance) Enzyme induction interactions 2 (Quality of Evidence: very low; theoretical, unknown clinical significance) Possible decreased efficacy of vincristine (8, 9) Possible increased toxicity of procarbazine (8, 9) Enzyme neutral agents 3 : unlikely to interact (Quality of Evidence: very low; theoretical) According to the metabolic profile of the individual agents, pharmacokinetic interactions are unlikely to occur. Nonetheless, additive toxicity remains possible with certain agents depending on the safety profile. Particularities regarding nucleoside reverse transcriptase inhibitor backbone (Quality of Evidence: very low; theoretical, unknown clinical significance) Potential additive renal toxicity with tenofovir (8, 9) Laboratory interactions (Quality of Evidence: high; no clinical significance) Cobicistat (Stribild, Tybost ), rilpivirine (Edurant, Complera ) and dolutegravir (Tivicay ) containing regimens will increase serum creatinine by approximately 7-15 µmol/l during the first 4 weeks of treatment initiation due to inhibition of renal creatinine secretion. This does not reflect an actual decrease in renal function, and the effect is quickly reversible upon drug discontinuation. Note: if interruption of any antiretroviral agent is considered necessary, contact the HIV physician to determine appropriate cessation of the antiretroviral therapy (certain antiretroviral regimens require sequential cessation of antiretroviral agents while others require immediate cessation of all antiretroviral agents at once). If treatment for hepatitis B (HBV) co-infection is required, consult the HIV physician, since some antiretroviral agents have activity against both HIV and HBV. A Wong, B.Pharm., M.Sc., McGill University Health Centre & A Tseng, Pharm.D., FCSHP, AAHIVP, Toronto General Hospital Page 1 of 4 November 2013 AGGRESSIVE HISTOLOGY NON-HODGKIN S LYMPHOMA - CNS LYMPHOMA 9

17 Antiretroviral-Chemotherapy Interactions: CNS lymphoma regimen Literature No studies or case reports specifically regarding high-dose methotrexate protocol and antiretroviral agents were found. Data available from other regimens including similar antineoplastic agents are presented below. CHOP One study evaluated the clinical impact of co-administration of combination antiretroviral therapy (cart) with CHOP (cyclophosphamide, doxorubicin, vincristine 1.4 mg/m 2 [max 2 mg], prednisone) in the context of treatment for non-hodgkin s lymphoma. In comparison to high-dose methotrexate protocol, the vincristine dose is the same; however it is given at each cycle unlike the current protocol. They did not observe any difference in response rates, dose intensity or number of cycles of chemotherapy when CHOP was co-administered in 24 patients with a PI based cart (saquinavir, indinavir or ritonavir) in comparison to 80 patients on CHOP alone. They did observe, however, an increased risk of grade 3 or 4 anemia and autonomic neurotoxicity. No difference was noted in regards to leucopenia, thrombocytopenia, mucositis or nausea. (6) It is important to note, however, that 58% of patients receiving cart had zidovudine in their regimen, likely explaining the increased risk of anemia. CODOX-M One case report described increased vincristine toxicity in the context of co-administration of CODOX-M (vincristine 4 mg IV, doxorubicin 40 mg/m 2 IV, cyclophosphamide 1600 mg/m 2 IV, cytarabine 140 mg IT, methotrexate 6720 mg/m 2 IV and methotrexate 15 mg IT per cycle) and lopinavir/ritonavir. The patient received one cycle of CODOX-M (vincristine 2 mg on D1 and D8) for treatment of Burkitt s lymphoma while on lopinavir/ritonavir based cart. Administered vincristine dose is largely superior to that given with high-dose methotrexate protocol. On Day 12, the patient developed paralytic ileus which lasted for 10 days. Two weeks after recovery, IVAC (ifosfamide 7.5 g/m 2 ; etoposide 300 mg/m 2 ; cytarabine 8 g/m 2 ) was administered with no complications. Two months after the first cycle, the patient was given CODOX-M; however, the vincristine component was changed to etoposide. This regimen, which included a higher IV methotrexate dose compared to the high dose methotrexate protocol, was well tolerated. (7) DA-EPOCH Two cases described good tolerability of dose-adjusted EPOCH (etoposide 200 mg/m 2, vincristine 1.6 mg/m 2, cyclophosphamide 748 mg/m 2, doxorubicin 40 mg/m 2 continuous infusion over 4 days, prednisone 60 mg/m 2 daily for 5 days) when administered with lopinavir/ritonavir for treatment of anaplastic large-cell lymphoma. Vincristine dose used is similar to that used in high-dose methotrexate protocol; however it was given at each cycle unlike the current protocol. (10) A Wong, B.Pharm., M.Sc., McGill University Health Centre & A Tseng, Pharm.D., FCSHP, AAHIVP, Toronto General Hospital Page 2 of 4 November AGGRESSIVE HISTOLOGY NON-HODGKIN S LYMPHOMA - CNS LYMPHOMA

18 Antiretroviral-Chemotherapy Interactions: CNS lymphoma regimen Metabolism of chemotherapy agents Chemotherapy agent Metabolism (8, 9) Possible interaction(8, 9) Clinical evidence Methotrexate Almost all drug is Increased monitoring of renal function with No methotrexate toxicity reported excreted unchanged concomitant tenofovir administration. in urine. in one case where CODOX- M/IVAC was administered with lopinavir/ritonavir for treatment of Burkitt s lymphoma. (7) Vincristine CYP 3A4 Possibility of increased levels leading to increased toxicity (peripheral and Possible increased risk of autonomic neurotoxicity when autonomic neuropathy, myelosuppression) administered with a PI based with CYP 3A4 inhibitors. Possibility of decreased levels with 3A4 inducers. regimen. (6, 7) Good tolerability in 2 cases with lopinavir/ritonavir and DA- EPOCH for treatment of anaplastic large-cell lymphoma.(10) Procarbazine Transformation to active metabolites: CYP2B6, 1A Inhibition of CYP1A or 2B isoenzymes may result in decreased efficacy of procarbazine. Induction of CYP1A or 2B6 by nelfinavir, tipranavir, efavirenz, nevirapine and ritonavir may potentially activity and/or toxicity. No studies or case reports found in the published literature. Please Antiretroviral-Chemotherapy consult Interactions: for more CNS updated lymphoma information. regimen References 1. Retrovir. Product monograph. GlaxoSmithKline; Combivir. Product Monograph. GlaxoSmithKline; Trizivir. Product Monograph. GlaxoSmithKline; Zerit. Product monograph. Bristol-Myers Squibb Canada; Videx Ec. Product monograph. Bristol-Myers Squibb Canada; Vaccher E, Spina M, di Gennaro G, Talamini R, Nasti G, Schioppa O, et al. Concomitant cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy plus highly active antiretroviral therapy in patients with human immunodeficiency virus-related, non-hodgkin lymphoma. Cancer Jan 1;91(1): Leveque D, Santucci R, Pavillet J, Herbrecht R, Bergerat JP. Paralytic ileus possibly associated with interaction between ritonavir/lopinavir and vincristine. Pharm World Sci Dec;31(6): Antoniou T, Tseng A. Potential interactions between antineoplastics and antiretrovirals. In: Tseng A, Foisy M, editors. Handbook of HIV drug therapy ed. Toronto2010. p Antoniou T, Tseng AL. Interactions between antiretrovirals and antineoplastic drug therapy. Clin Pharmacokinet. 2005;44(2): Nagajothi N, Dham SK, Gelfand Y, Sanmugarajah J. Treatment of AIDS-associated anaplastic large-cell lymphoma with dose-adjusted EPOCH chemotherapy. J Natl Med Assoc. [Case Reports] Jul;99(7): Enzyme inhibitors include protease inhibitors (PIs): Crixivan (indinavir), Invirase (saquinavir), Kaletra (lopinavir/ritonavir), Norvir, Norvir sec (ritonavir), Prezista (darunavir), Reyataz (atazanavir), Telzir (fosamprenavir), Viracept (nelfinavir); and the integrase inhibitor elvitegravir/cobicistat: available as a coformulated product with tenofovir/emtrictabine (Stribild ); pharmacokinetic enhancer cobicistat (Tybost ). A 2 Enzyme Wong, B.Pharm., inducers include M.Sc., non-nucleside McGill University reverse Health transcriptase Centre & A inhibitors Tseng, Pharm.D., (NNRTIs): FCSHP, Atripla AAHIVP, Toronto General Hospital (efavirenz/tenofovir/emtricitabine), Complera (rilpivirine/tenofovir/emtricitabine), Edurant (rilpivirine), Intelence (etravirine), Sustiva (efavirenz), Page 3 of Viramune, 4 Viramune XR November (nevirapine) 2013 and the protease inhibitor Aptivus (tipranavir) 3 Enzyme neutral agents include nucleoside reverse transcriptase inhibitors (NRTIs) : 3TC (lamivudine), Combivir (lamivudine/zidovudine), Kivexa (abacavir/lamivudine), Retrovir (zidovudine), Trizivir (abacavir/zidovudine/lamivudine), Truvada (tenofovir/emtricitabine), Videx EC (didanosine), Zerit (stavudine); integrase inhibitors Isentress (raltegravir), Tivicay (dolutegravir); entry inhibitors Fuzeon (enfuvirtide), Celsentri (maraviroc) AGGRESSIVE HISTOLOGY NON-HODGKIN S LYMPHOMA - CNS LYMPHOMA 11

19 Antiretroviral-Chemotherapy Interactions: CODOX-M regimen Chemotherapy regimen: CODOX-M Agents involved Vincristine 1.4 mg/m 2 IV Day 1, 8 Doxorubicin 50 mg/m 2 IV Day 1 Cyclophosphamide 800 mg/m 2 IV in 500 ml of NS Day 1 2 Cytarabine 50 mg IT Days 1, 3 Methotrexate 3000 mg/m 2 IV in 500 ml of D5W Day 10 Methotrexate 12 mg IT Day 15 Summary of possible interactions with antiretroviral agents Antiretroviral agents to avoid Avoid zidovudine-containing regimens (Retrovir, Combivir, Trizivir ) as additive hematologic toxicity is possible (1-3). (Quality of Evidence: very low) Avoid stavudine (Zerit ), didanosine (Videx EC ) due to possible additive peripheral neuropathy (4, 5). (Quality of Evidence: very low) If the patient is on one of the antiretroviral agents mentioned above, contact the HIV physician to request a change/substitution of antiretroviral agents. Enzyme inhibition interactions 1 Possible increased vincristine toxicity autonomic neurotoxicity) (6, 8) (Quality of Evidence: moderate) Possible increased cyclophosphamide toxicity due to decreased clearance (9) (Quality of Evidence: very low; pharmacokinetic study of unknown clinical significance) Enzyme induction interactions 2 (Quality of Evidence: very low; theoretical, unknown clinical significance) Possible decreased efficacy of doxorubicin and vincristine (10, 11) Possible decreased efficacy and increase in cyclophosphamide toxicity due to increased inactivation to toxic metabolites (10, 11) Enzyme neutral agents 3 : unlikely to interact (Quality of Evidence: very low; theoretical) According to the metabolic profile of the individual agents, pharmacokinetic interactions are unlikely to occur. Nonetheless, additive toxicity remains possible with certain agents depending on the safety profile. Particularities regarding nucleoside reverse transcriptase inhibitor backbone (Quality of Evidence: very low; theoretical, unknown clinical significance) Potential additive renal toxicity with tenofovir (10, 11) Laboratory interactions (Quality of Evidence: high; no clinical significance) Cobicistat (Stribild, Tybost ), rilpivirine (Edurant, Complera ) and dolutegravir (Tivicay ) containing regimens will increase serum creatinine by approximately 7-15 µmol/l during the first 4 weeks of treatment initiation due to inhibition of renal creatinine secretion. This does not reflect an actual decrease in renal function, and the effect is quickly reversible upon drug discontinuation. Note: if interruption of any antiretroviral agent is considered necessary, contact the HIV physician to determine appropriate cessation of the antiretroviral therapy (certain antiretroviral regimens require sequential cessation of antiretroviral agents while others require immediate cessation of all antiretroviral agents at once). If treatment for hepatitis B (HBV) co-infection is required, consult the HIV physician, since some antiretroviral agents have activity against both HIV and HBV. AGGRESSIVE HISTOLOGY NON-HODGKIN S LYMPHOMA - CODOX-M 13